The goal of this study is to identify dendritic abnormalities in hippocampal neurons from humans with major depression. In laboratory animals, stress and glucocorticoids have been shown to result in atrophy of pyramidal cells in hippocampal region CA3.These models have long been assumed to represent depression, and the dendritic atrophy that they reveal is an obvious candidate to underlie hippocampal volume deficits observed by in vivo imaging of depressed patients. Surprisingly, except for a few cases included in our earlier studies of schizophrenia, hippocampal dendritic morphology in major depressive disorder has been unexamined, in part, no doubt, because of the difficulty of obtaining appropriately stained material. Using a new modification of the Golgi-Cox technique, we are accumulating a sizable collection of well-impregnated hippocampi from well-characterized subjects with DSM IV defined major depression or without psychiatric illness. This modification, which we call NeoGolgi, consistently yields a uniform impregnation of all regions in the section, permitting uniform random sampling of neurons for analysis. We propose to analyze dendritic arborization and spine density in the hippocampi of 30 subjects with major depressive disorder, and 30 nonpsychiatric subjects matched for age and sex. We will include granular cells from the dentate gyrus and pyramidal cells from CA3, CA1, and subiculum: the intrinsic hippocampal trisynaptic pathway and its major output. The proposed study should be sufficiently large and comprehensive to resolve the question of whether there are significant hippocampal dendritic deficits in major depressive disorder. Furthermore, since approximately one-third of our proposed sample of major depression subjects was never treated and died within one year of the onset of illness, we will be able to address the question of whether any deficits observed are the result of chronic illness or treatment. We also propose to measure hippocampal levels of brain-derived neurotrophic factor (BDNF), in order to determine whether these are correlated with neuronal morphology, as suggested by animal models, and whether such correlations are affected by major depression (associated with low BDNF levels), or with antidepressant treatment, which is associated with higher levels. Finally, in order to facilitate exploration of the relationship between dendritic morphology and specific afferent connections, we will attempt to develop techniques to combine immunohistochemistry and high-quality Golgi staining. PUBLIC HEALTH RELEVANCE Major depressive disorder is a common illness that causes much disability and death. It has long been suspected that major depressive disorder involves structural abnormalities of the brain, including shrinkage of nerve cell projections that receive information from other nerve cells, but this hypothesis has never been tested. Verifying and localizing such abnormalities, as we propose, will tell us much about what is wrong with the brain in this illness and whether it can be repaired.